As a process for producing a 3-aralkyloxypyrrolidine derivative (2), following methods are conventionally used.    (i) After 4M hydrogen chloride in anhydrous dioxane is added to N-Boc-3-benzyloxypyrrolidine at 0° C., the mixture is concentrated, and dissolved in toluene. After stirring, syrupy 3-benzyloxypyrrolidine is obtained (for example, refer to Patent document 1).    (ii) 4-benzyloxypyrrolidine-2-on is reduced with LiAlH4 to obtain 3-benzyloxypyrrolidine (for example, refer to Nonpatent literature 1).    (iii) (R)—N-Boc-3-benzyloxypyrrolidine is stirred in 90% aqueous solution of formic acid at from 0° C. to room temperature and the solvent is distilled away under reduced pressure, and then the resultant residue is neutralized with an aqueous solution of K2CO3. After the aqueous solution is extracted with n-butanol, the solvent is removed under reduced pressure and then treated by silica gel column chromatography, thereby obtaining (R)-3-benzyloxypyrrolidine (for example, refer to Patent document 2 and Nonpatent literature 2).
However, as described in the method (i), since a 3-aralkyloxypyrrolidine derivative (2) such as 3-benzyloxypyrrolidine hydrochloride is not suitable in terms of affinity with various solvents, particularly nonpolar solvents such as hydrocarbon solvents, the 3-aralkyloxypyrrolidine derivative (2) turns into oil form in a solvent comprising these solvents as a main solvent, so that a suitable crystallization thereof is difficult. Additionally, properties of the substance such as moisture absorption property are not known almost at all, and there has been no disclosure as to problems in treating the substance on an industrial scale and solutions for the problems.
With respect to (ii), since LiAlH4 is used as a reaction reagent, the method has a danger of generating hydrogen at a time of reaction and requires troublesome treatments in disposing aluminum generated as by-product after the reaction, and there is a substantial problem in production on a commercial scale. Additionally, in a case where 4-benzyloxypyrrolidine-2-on is reduced by the method, since resultant 3-hydroxypyrrolidine is a racemate, it is not a suitable method when a desired substance is optically active 3-aralkyloxypyrrolidine.
With respect to a purification method of 3-aralkyloxypyrrolidine, a purification method by column chromatography according to the method (iii) is disclosed, but there are problems in production on a commercial scale such as unfavorable heavy consumption of solvents, complexity of processes and an accompanying waste of time, increase in the number and capacity of production apparatus, and decrease in yield.
As described above, with respect to the 3-aralkyloxypyrrolidine derivative (2) such as 3-benzyloxypyrrolidine, there is no disclosure of a crystallization method thereof, an industrially efficient purification method, and a method for handling thereof, so that there is a demand for developing a method of industrially and conveniently crystallizing the compound and a purification method for obtaining the compound with high purity, and a suitable method for handling on an industrial scale.
Further, with respect to a process for producing N-protected-3-aralkyloxypyrrolidine (1) which is a raw material of the present invention, there is known a method converting from a N-protected-3-hydroxypyrrolidine (5); for example, a method allowing benzyl bromide to act in the presence of NaH (for example, Nonpatent literature 2) in an organic solvent is known; the N-protected-3-aralkyloxypyrrolidine (1) and the N-protected-3-hydroxypyrrolidine (5) are represented by:
wherein P represents a protecting group of an amino group; and R represents the same as above; and
wherein P represents a protecting group of an amino group. However, in the above method, NaH has dangers of hydrogen generation and ignition by contact with moisture, and benzyl bromide is substantially difficult to obtain on an industrial scale due to having a strong tearing property. Therefore, the above method is not necessarily a suitable process for producing N-protected-3-aralkyloxypyrrolidine industrially.    [Patent document 1] Japanese unexamined patent publication No. 1-311059    [Patent document 2] WO9604274    [Nonpatent literature 1] Synlett 2004, No. 10, 1763-1764    [Nonpatent literature 2] J. Med. Chem., 1999, 42, 677-690